Disruption of brain-derived neurotrophic factor production from individual promoters generates distinct body composition phenotypes in mice

Liam McAllan, Kristen R. Maynard, Alisha S. Kardian, Amanda S. Stayton, Shelby L. Fox, Erin J. Stephenson, Clint E. Kinney, Noor K. Alshibli, Charles K. Gomes, Joseph Pierre, Michelle Puchowicz, Dave Bridges, Keri Martinowich, Joan Han

Research output: Contribution to journalArticle

Abstract

Brain-de-rived neurotrophic factor (BDNF) is a key neuropeptide in the central regulation of energy balance. The Bdnf gene contains nine promoters, each producing specific mRNA transcripts that encode a common protein. We sought to assess the phenotypic outcomes of disrupting BDNF production from individual Bdnf promoters. Mice with an intact coding region but selective disruption of BDNF production from Bdnf promoters I, II, IV, or VI (Bdnf-e1/,-e2/,-e4/, and-e6/) were created by inserting an enhanced green fluorescent protein-STOP cassette upstream of the targeted promoter splice donor site. Body composition was measured by MRI weekly from age 4 to 22 wk. Energy expenditure was measured by indirect calorimetry at 18 wk. Food intake was measured in Bdnf-e1/ and Bdnf-e2/ mice, and pair feeding was conducted. Weight gain, lean mass, fat mass, and percent fat of Bdnf-e1/ and Bdnf-e2/ mice (both sexes) were significantly increased compared with wild-type littermates. For Bdnf-e4/ and Bdnf-e6/ mice, obesity was not observed with either chow or high-fat diet. Food intake was increased in Bdnf-e1/ and Bdnf-e2/ mice, and pair feeding prevented obesity. Mutant and wild-type littermates for each strain (both sexes) had similar total energy expenditure after adjustment for body composition. These findings suggest that the obesity phenotype observed in Bdnf-e1/ and Bdnf-e2/ mice is attributable to hyperphagia and not altered energy expenditure. Our findings show that disruption of BDNF from specific promoters leads to distinct body composition effects, with disruption from promoters I or II, but not IV or VI, inducing obesity.

Original languageEnglish (US)
Pages (from-to)E1168-E1184
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume315
Issue number6
DOIs
StatePublished - Dec 1 2018

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Brain-Derived Neurotrophic Factor
Body Composition
Nerve Growth Factors
Phenotype
Obesity
Energy Metabolism
Brain
Eating
Fats
Hyperphagia
Indirect Calorimetry
RNA Splice Sites
High Fat Diet
Neuropeptides
Weight Gain
Messenger RNA
Genes
Proteins

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

Cite this

Disruption of brain-derived neurotrophic factor production from individual promoters generates distinct body composition phenotypes in mice. / McAllan, Liam; Maynard, Kristen R.; Kardian, Alisha S.; Stayton, Amanda S.; Fox, Shelby L.; Stephenson, Erin J.; Kinney, Clint E.; Alshibli, Noor K.; Gomes, Charles K.; Pierre, Joseph; Puchowicz, Michelle; Bridges, Dave; Martinowich, Keri; Han, Joan.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 315, No. 6, 01.12.2018, p. E1168-E1184.

Research output: Contribution to journalArticle

McAllan, L, Maynard, KR, Kardian, AS, Stayton, AS, Fox, SL, Stephenson, EJ, Kinney, CE, Alshibli, NK, Gomes, CK, Pierre, J, Puchowicz, M, Bridges, D, Martinowich, K & Han, J 2018, 'Disruption of brain-derived neurotrophic factor production from individual promoters generates distinct body composition phenotypes in mice', American Journal of Physiology - Endocrinology and Metabolism, vol. 315, no. 6, pp. E1168-E1184. https://doi.org/10.1152/ajpendo.00205.2018
McAllan, Liam ; Maynard, Kristen R. ; Kardian, Alisha S. ; Stayton, Amanda S. ; Fox, Shelby L. ; Stephenson, Erin J. ; Kinney, Clint E. ; Alshibli, Noor K. ; Gomes, Charles K. ; Pierre, Joseph ; Puchowicz, Michelle ; Bridges, Dave ; Martinowich, Keri ; Han, Joan. / Disruption of brain-derived neurotrophic factor production from individual promoters generates distinct body composition phenotypes in mice. In: American Journal of Physiology - Endocrinology and Metabolism. 2018 ; Vol. 315, No. 6. pp. E1168-E1184.
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